Molecular Hybridization Strategy for Developing Lipid‐Lowering Compounds: Design and Synthesis of Vanillin‐Based Fibrate Derivatives

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In this research, we developed and synthesized a range of fibrate derivatives based on vanilla using molecular hybridization techniques. The lipid-lowering effects of target compounds was performed on Triton WR-1339-induced hyperlipidemic mouse model, where T2 showed the best anti-hyperlipidemia activity, reducing total cholesterol (TC) and triglycerides (TG) significantly. The hypolipidemic activity of T2 also showed the dose-dependent action. T2 was shown to notably enhance lipid metabolism issues in mice that had hyperlipidemia caused by a high-fat diet (HFD). Among them, blood lipid indicators such as TG, TC, and LDL-C were significantly regulated by T2, and their levels show a significant downward trend. T2 significantly upregulates the expression of peroxisome proliferator-activated receptor alpha (PPAR-α) protein and shows a strong binding affinity for the active site of the PPAR-α receptor. T2 exhibits hepatoprotective effects by markedly lowering serum and hepatic levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Studies have shown that T2 administration can lessen the buildup of lipids in the liver, offering a protective benefit against liver damage. In addition, T2 also exhibits significant anti-inflammatory and antioxidant effects. Therefore, T2 may serve as a potential novel and effective lipid-lowering compound with hepatoprotective properties.

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